L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and thus is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called EAA receptors. The EAA receptors are of great physiological importance playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, emotional states and sensory perception.
The excessive or inappropriate stimulation of EAA receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. The medical consequence of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutical goal.
EAA receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membranes of the neuron are termed xe2x80x9cionotropicxe2x80x9d. The second type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d EAA receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function. The metabotropic glutamate receptors (mGluR) have been distinguished pharmacologically from the ionotropic glutamate receptors by the use of the metabotropic glutamate-selective antagonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, generally through measurements involving phosphoinositide hydrolysis or Ca2+ mobilization. To date the use of expression cloning techniques has led to the identification of eight mGluR subtypes, which have been placed into three major categories (Groups) based on their molecular structure, signal transduction mechanisms, and pharmacological properties. Group I mGluRs (mGluR1 and 5) are coupled to phosphoinositide (PI) hydrolysis, whereas Group II (mGluR2 and 3) and Group III (mGluR4, 6, 7, and 8) are negatively linked to adenylyl cyclase activity.
Glutamate receptors play a role in numerous neurological, neurodegenerative, psychiatric, and psychological disorders, and a variety of mammalian disease states are associated with xe2x80x9cabnormal activityxe2x80x9d of these receptors. As used herein, the term xe2x80x9cabnormal activatyxe2x80x9d includes either an increase or a decrease in activation of the receptors as compared to normal function in said mammal. For example, metabotropic glutamate receptor ligands should be useful in the treatment of diseases or conditions including epilepsy, cerebral ischemia, pain, anxiety, spinal cord injury, chronic neurodegenerative diseases (e.g. Alzheimer""s disease), Lou Gherig""s disease (ALS), Parkinson""s disease, Multiple Sclerosis and other diseases or conditions that result in progressive loss of neuronal cells and or cellular function.
In order to better characterize the roles of mGluRs in physiological processes, there is a need to identify novel, high affinity compounds that are mGluR Group or subtype specific. Such compounds are needed for use as pharmacological tools for the further investigation of mGluR function, and should be useful as therapeutic agents for the treatment of diseases or conditions associated with abnormal activity of metabotropic glutamate receptors.
The present invention provides compounds that are ligands for metabotropic glutamate receptors. Accordingly there is provided a compound of the invention which is a bicyclic compound of formula I: 
wherein
R1, R2, R3, R4, R7, R8, R9, and R10 are each independently hydrogen, carboxy, tetrazolyl, xe2x80x94SO2OH, xe2x80x94PO(OH)2, xe2x80x94B(OH)2, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, halo, xe2x80x94CONRaRb, xe2x80x94NRcRdxe2x80x94SRe, aryl, heteroaryl, aryl(C1-C6)alkyl, diaryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, wherein any aryl or heteroaryl may optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of halo, hydroxy, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, and carboxy;
R5 is carboxy, tetrazolyl, (C1-C6)alkoxycarbonyl, xe2x80x94SO2OH, xe2x80x94B(OH)2, or xe2x80x94PO(OH)2;
R6 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, or (C1-C6)alkanoyl;
X is absent (a direct or single bond connects C3 and C4), oxy (xe2x80x94Oxe2x80x94), thio (xe2x80x94Sxe2x80x94), sulfinyl (xe2x80x94SOxe2x80x94), sulfonyl (xe2x80x94SO2xe2x80x94), xe2x80x94C(Rf)(Rg)xe2x80x94, seleno (xe2x80x94Sexe2x80x94), xe2x80x94P(Rx)xe2x80x94, or xe2x80x94N(Rx)xe2x80x94, wherein Rx is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, aryl, aryl(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, or aryl(C1-C6)alkoxycarbonyl;
each Ra Rb and Rc is independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, benzyl, or phenethyl;
each Rc or Rd is independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, aryl, heteroaryl, benzyl, or phenethyl; or Rc and Rd together with the nitrogen to which they are attached are triazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;
Rf and Rg are each independently hydrogen, carboxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, halo, xe2x80x94CONRhRi, xe2x80x94NRjRk, xe2x80x94SRm, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, wherein any aryl or heteroaryl may optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of halo, hydroxy, (C1-C6)alkoxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, and carboxy; or Rf and Rg together are oxo (xe2x95x90O) or thioxo (xe2x95x90S);
each Rh, and Ri, and Rm is independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, benzyl, or phenethyl; and
each Rj or Rk is independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, aryl, heteroaryl, benzyl, or phenethyl; or Rj and Rk together with the nitrogen to which they are attached are triazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;
or a pharmaceutically acceptable salt or prodrug thereof;
wherein at least one of R1, R2, R3, R4, R9, and R10 is carboxy, tetrazolyl, xe2x80x94SO2OH, xe2x80x94PO(OH)2, or xe2x80x94B(OH)2.
The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable diluent or carrier.
Additionally, the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, which is associated with abnormal activity of metabotropic glutamate receptors, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof.
The invention provides a compound of formula I for use in medical diagnosis or therapy (preferably for use in treating a pathological condition or symptom in a mammal, such as a human, associated with abnormal activity of metabotropic glutamate receptors), as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated with abnormal activity of metabotropic glutamate receptors.
The invention provides a method for binding a compound of formula I to metabotropic glutamate receptors comprising contacting mammalian tissue comprising said receptors, in vivo or in vitro, with an amount of a compound of formula I effective to bind to said receptors. Tissue comprising ligand bound metabotropic glutamate receptors can be used to measure the selectivity of test compounds for specific mGluR Groups or subtypes, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with abnormal activation of metabotropic glutamate receptors, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent.
The invention also provides compounds of formula I comprising a label (e.g a detectable radionuclide such as 3H, 11C, 14C, or 13N, or a detectable nonradioactive nuclide such as 2H, 13C, 15N, or 18O), and their use e.g. in stuties of receptor function or in the elucidation of the structure, function or mechanism of competitive ligand interaction. Techniques and radionuclides suitable for labeling compounds for in vivo or in vitro detection are well known to the art.